Vraylar (Cariprazine) Dosing and Side Effects
Vraylar is dosed once daily starting at 1.5 mg for schizophrenia and bipolar depression, with titration based on indication, and carries a black box warning for increased mortality in elderly patients with dementia-related psychosis and suicidal thoughts/behaviors in young adults. 1
FDA-Approved Indications
Vraylar (cariprazine) is approved for: 1
- Schizophrenia in adults
- Acute manic or mixed episodes associated with bipolar I disorder in adults
- Bipolar depression (depressive episodes associated with bipolar I disorder) in adults
- Adjunctive therapy to antidepressants for major depressive disorder (MDD) in adults
Dosing Recommendations by Indication
Schizophrenia 1
- Starting dose: 1.5 mg orally once daily
- Day 2: Can increase to 3 mg once daily
- Recommended range: 1.5-6 mg once daily
- Titration: Can adjust in 1.5 mg or 3 mg increments based on response and tolerability
- Maximum dose: 6 mg once daily (doses above 6 mg do not provide sufficient benefit to outweigh adverse reactions)
Bipolar Mania (Manic or Mixed Episodes) 1
- Starting dose: 1.5 mg orally once daily
- Day 2: Increase to 3 mg once daily
- Recommended range: 3-6 mg once daily
- Titration: Can adjust in 1.5 mg or 3 mg increments
- Maximum dose: 6 mg once daily
Bipolar Depression 1
- Starting dose: 1.5 mg orally once daily
- Day 15: Can increase to 3 mg once daily based on response
- Maximum dose: 3 mg once daily
Adjunctive Therapy for Major Depressive Disorder 1
- Starting dose: 1.5 mg orally once daily
- Day 15: Can increase to 3 mg once daily based on response
- Maximum dose: 3 mg once daily
- Critical timing: Titration intervals less than 14 days resulted in higher incidence of adverse reactions in clinical trials
Important Pharmacokinetic Considerations
Due to the extremely long half-life of cariprazine and its active metabolites (2-5 days for cariprazine, 2-3 weeks for the active didesmethyl-cariprazine metabolite), changes in dose will not be fully reflected in plasma for several weeks. 1, 2 Prescribers must monitor patients for adverse reactions and treatment response for several weeks after starting Vraylar and after each dosage change. 1
Drug Interactions Requiring Dose Adjustments
Strong CYP3A4 Inhibitors 1
When initiating Vraylar while taking a strong CYP3A4 inhibitor:
- Schizophrenia: Start at 1.5 mg every 3 days; increase to 1.5 mg every other day if needed
- Bipolar mania, bipolar depression, or adjunctive MDD: 1.5 mg every 3 days
When initiating a strong CYP3A4 inhibitor while on stable Vraylar:
- If on 1.5 or 3 mg daily → reduce to 1.5 mg every 3 days
- If on 4.5 or 6 mg daily → reduce to 1.5 mg every other day
Moderate CYP3A4 Inhibitors 1
When initiating Vraylar while taking a moderate CYP3A4 inhibitor:
- Schizophrenia: Start at 1.5 mg every other day; increase to 1.5 mg daily if needed
- Bipolar mania, bipolar depression, or adjunctive MDD: 1.5 mg every other day
When initiating a moderate CYP3A4 inhibitor while on stable Vraylar:
- If on 1.5 or 3 mg daily → reduce to 1.5 mg every other day
- If on 4.5 or 6 mg daily → reduce to 1.5 mg daily
Black Box Warnings
Increased Mortality in Elderly Patients with Dementia-Related Psychosis 1
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at increased risk of death. Vraylar is NOT approved for treatment of patients with dementia-related psychosis.
Suicidal Thoughts and Behaviors 1
Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Close monitoring is required for all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors. Vraylar is not approved for use in pediatric patients.
Common Side Effects
Schizophrenia (≥5% and at least twice placebo rate) 1
- Extrapyramidal symptoms (EPS): Including bradykinesia, cogwheel rigidity, drooling, dyskinesia, dystonia, muscle rigidity, tremor
- Akathisia: One of the most common movement-related side effects
Bipolar Mania (≥5% and at least twice placebo rate) 1
- Extrapyramidal symptoms
- Akathisia (led to 2% discontinuation rate)
- Dyspepsia
- Vomiting
- Somnolence
- Restlessness
Additional Common Adverse Reactions (≥2% and greater than placebo) 1
- Headache
- Insomnia
- Hypertension
- Elevated liver enzymes (ALT, AST)
Serious Warnings and Precautions
Neuroleptic Malignant Syndrome (NMS) 1
A potentially fatal symptom complex that can occur with antipsychotic drugs. Monitor for hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability.
Tardive Dyskinesia 1
Risk of developing potentially irreversible involuntary dyskinetic movements increases with duration of treatment and total cumulative dose. Consider discontinuation if tardive dyskinesia appears.
Metabolic Changes 1
Monitor for:
- Hyperglycemia and diabetes mellitus
- Dyslipidemia
- Weight gain (though cariprazine is associated with less weight gain compared to some other atypical antipsychotics) 3, 2
Orthostatic Hypotension and Syncope 1
Can cause orthostatic hypotension and syncope, especially during initial dose titration. Use caution in patients with cardiovascular or cerebrovascular disease.
Falls 1
Antipsychotics including Vraylar may cause somnolence, postural hypotension, and motor/sensory instability, leading to falls and fall-related injuries.
Leukopenia, Neutropenia, and Agranulocytosis 1
Monitor complete blood count in patients with pre-existing low white blood cell count or history of drug-induced leukopenia/neutropenia.
Cognitive and Motor Impairment 1
Patients should be cautioned about operating hazardous machinery, including motor vehicles, until reasonably certain that Vraylar does not affect them adversely.
Body Temperature Dysregulation 1
Use caution in patients who may experience strenuous exercise, extreme heat exposure, dehydration, or concurrent anticholinergic medications.
Seizures 1
Use cautiously in patients with a history of seizures or conditions that lower the seizure threshold.
Dysphagia 1
Esophageal dysmotility and aspiration risk; use cautiously in patients at risk for aspiration.
Clinical Efficacy Evidence
Cariprazine demonstrated significant efficacy across the psychosis spectrum in a 2024 network meta-analysis of 12 randomized controlled trials (n=6,477 patients). 4 The drug effectively reduced:
- Global clinical severity: Greater improvements at higher doses (-0.25 at ≤1.5 mg/day, -0.45 at ≥3 mg/day)
- Psychotic symptoms: -6.74 points (95% CI -8.31 to -5.17)
- Depression: -1.78 points (95% CI -2.54 to -1.02)
- Mania: -5.72 points (95% CI -6.95 to -4.49)
- Anxiety: -1.24 points (95% CI -1.92 to -0.56)
Cariprazine showed particular efficacy for negative symptoms of schizophrenia, demonstrating superiority over risperidone in patients with predominantly negative symptoms. 5, 6 This is attributed to its ten-fold greater affinity for dopamine D3 receptors compared to D2 receptors. 3, 6
Key Advantages Over Other Atypical Antipsychotics
- Lower metabolic burden: Fewer incidents of weight gain, diabetes, hyperlipidemia, and metabolic abnormalities compared to many other atypical antipsychotics 3, 2, 6
- No prolactin elevation: Does not cause clinically significant prolactin increases 2
- No QT prolongation: Does not cause corrected QT interval prolongation 2
- Better relapse prevention: Demonstrated significantly longer time to relapse than placebo in long-term studies 5
Critical Clinical Pitfalls
The extremely long half-life (2-3 weeks for active metabolite) means adverse effects may emerge or persist weeks after dose changes or discontinuation. 1, 2 Clinicians must counsel patients about this delayed effect and maintain vigilant monitoring for several weeks after any dosing adjustment.
Extrapyramidal symptoms and akathisia, while generally mild to moderate, occur more frequently than with placebo and can lead to treatment discontinuation. 1, 3 Early recognition and management (dose reduction or adjunctive treatment) is essential for maintaining adherence.